US20220402911A1 - Novel compounds and pharmaceutical compositions thereof for the treatment of diseases - Google Patents

Novel compounds and pharmaceutical compositions thereof for the treatment of diseases Download PDF

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US20220402911A1
US20220402911A1 US17/252,146 US201917252146A US2022402911A1 US 20220402911 A1 US20220402911 A1 US 20220402911A1 US 201917252146 A US201917252146 A US 201917252146A US 2022402911 A1 US2022402911 A1 US 2022402911A1
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methoxy
independently selected
pyridin
imidazo
difluoromethoxy
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David Amantini
Reginald Christophe Xavier Brys
Denis Bucher
Steve Irma Joel De Vos
Nicolas Desroy
Agnès Marie JONCOUR
Christophe Peixoto
Taoues TEMAL-LAÏB
Amynata Tirera
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Galapagos NV
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Galapagos NV
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Priority claimed from GBGB1809836.8A external-priority patent/GB201809836D0/en
Priority claimed from GBGB1817344.3A external-priority patent/GB201817344D0/en
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Assigned to GALAPAGOS NV reassignment GALAPAGOS NV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRYS, REGINALD CHRISTOPHE XAVIER, DE VOS, STEVE IRMA JOEL, AMANTINI, DAVID, JONCOUR, Agnès Marie, TIRERA, Amynata, BUCHER, Denis, DESROY, NICOLAS, PEIXOTO, CHRISTOPHE, TEMAL-LAÏB, Taoues
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • the compounds of the invention may inhibit Salt-Inducible Kinases (“SIK” kinases).
  • Protein kinases belong to a large family of structurally related enzymes which are responsible for the control of a wide variety of cellular signal transduction processes. In particular, they have been shown to be key regulators in cellular functions including for example proliferation, metabolism, and apoptosis.
  • IL-10 interleukin-10
  • AMPK Adenosine Monophosphate-activated Protein Kinases
  • SIKs Salt-Inducible Kinases
  • SIK1 also referred as SNFI-Like Kinase (SNFILK) or Myocardial Snfl-Iike Kinase (MSK)
  • SIK2 SNF1LK2 or KIAA0781
  • SIK3 SIK3 (KIAA0999) (Katoh et al. 2004).
  • the SIKs play a number of roles in different cell types. They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and Histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.
  • CRTC CREB-responsive transcriptional co-activator
  • HDAC Histone de-acetylase
  • One of the roles of CRTC signalling relates to control the phenotype of macrophages, in particular polarisation of macrophages through phosphorylation of CRTC3 as measured by decreased proinflammatory cytokine IL-12 secretion and concomitant increased pro-resolution cytokine IL-10 secretion (Clark et al. 2012; Ozanne et al. 2015).
  • SIK1 has recently been shown to be involved in skeletal muscle sensitivity in obese mice, and may be an interesting target to prevent type II diabetes (Nixon et al. 2016), and diabetic nephropathy (Yu et al. 2013).
  • SIK1 The regulation of ALK5 by SIK1 (Yu et al. 2013) and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis (Liu et al. 2013) suggest a role for SIK proteins in fibrotic diseases.
  • SIK2 and SIK3 have recently been identified to play a role in inflammation through the secretion of high levels of anti-inflammatory cytokines, in particular Interleukin-10 (IL-10) and very low levels of pro-inflammatory cytokines such as TNF ⁇ (Darling et al. 2017).
  • IL-10 Interleukin-10
  • TNF ⁇ pro-inflammatory cytokines
  • SIK2 may be an interesting target for inflammatory diseases (Yao et al. 2013).
  • small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2.
  • Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice (Wein et al. 2016), confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.
  • SIK2 after oxygen-glucose deprivation enhances neuron survival (Sasaki et al. 2011) or promotes melanogenesis in melanoma cells (Kumagai et al. 2011).
  • therapeutic strategies are needed to modulate the stress cellular response, such as during ischaemia and post reperfusion of tissue, in the chronic phase of cardiac remodelling, in diabetes and neurodegenerative conditions, the rapid activation or degradation of the SIK proteins, following multiple kinds of stresses, makes them interesting targets in inflammatory, cardiac or metabolic diseases and neurodegenerative disorders.
  • SIK inhibition might also have application in cosmetology or pigmentation-related diseases to induce melanogenesis.
  • SIK1 The regulation of ALK5 by SIK1 (Yu et al. 2013) and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis (Liu et al. 2013) suggest a role for SIK proteins in fibrotic diseases.
  • SIK proteins Besides the pivotal function in cellular energy homeostasis, the SIK proteins have also been involved in the regulation of the cell cycle. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers (Ashour Ahmed et al. 2010), moreover, expression of SIK3 was elevated in ovarian cancers, particularly in the serous subtype and at later stages (Charoenfuprasert et al. 2011). Therefore SIK inhibition may be useful in the treatment of cancer.
  • FIG. 1 refers to Example 4.2 and shows the evolution of the clinical score in the CIA mouse model for the vehicle (filled diamonds), Enbrel® (filled squares), Cpd 88 dosed at 10 mg/kg b.i.d. (crosses), Cpd 88 dosed at 30 mg/kg b.i.d. (triangles) and Cpd 88 dosed at 60 mg/kg b.i.d. (asterisks)
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention may be SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL
  • the compounds of the invention are provided having a Formula I.
  • X is N or CH
  • Y is N or CR 2b ;
  • the compounds of the invention are provided for use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological
  • the compounds of the invention exhibit potency against SIK, particularly SIK1, SIK2 and/or SIK3, more particularly SIK2 and/or SIK3, which may result in a tolerogenic therapy (i.e. reduction of pro-inflammatory cytokines such as TNF ⁇ and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF- ⁇ ).
  • a tolerogenic therapy i.e. reduction of pro-inflammatory cytokines such as TNF ⁇ and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF- ⁇ .
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • analogue means one analogue or more than one analogue.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (—CH 3 ), ethyl (—CH 2 —CH 3 ), n-propyl (—CH 2 —CH 2 —CH 3 ), isopropyl (—CH(CH 3 ) 2 ), n-butyl (—CH 2 —CH 2 —CH 2 —CH 3 ), tert-butyl (—C(CH 3 ) 3 ), sec-butyl (—CH(CH 3 )—CH 2 CH 3 ), isobutyl (—CH 2 —CH(CH 3 ) 2 ), n-pentyl (—CH 2 —CH 2 —CH 2 —CH 2 —CH 3 ), n-hexyl (—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 3 ), and 1,2-dimethylbutyl (—CHCH 3 )—C(CH 3 )H 2 —CH 2 —CH 3 ).
  • Particular alkyl groups have between 1 and
  • alkenyl refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl (—C(CH 3 ) ⁇ CH 2 ) and the like.
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (—CH 2 —), ethylene (—CH 2 —CH 2 —), or —CH(CH 3 )— and the like.
  • Alkynylene refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as —C ⁇ C—, —CH 2 —C ⁇ C—, and —C(CH 3 )H—C ⁇ CH—.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group —O—C 1-6 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical —NH 2 .
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cyano refers to the radical —CN.
  • Halo or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • polycyclic refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • Heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • heteroaryls examples include the following:
  • each Y is selected from >C ⁇ O, NH, O and S.
  • Heterocycloalkyl means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.
  • heterocycloalkenyl means a ‘heterocycloalkyl’, which comprises at least one double bond.
  • heterocycloalkenyl groups are shown in the following illustrative examples:
  • each W is selected from CH 2 , NH, O and S; each Y is selected from NH, O, C( ⁇ O), SO 2 , and S; and each Z is selected from N or CH.
  • each W and Y is independently selected from —CH 2 —, —NH—, —O— and —S—.
  • each W and Y is independently selected from —CH 2 —, —NH—, —O— and —S—.
  • each W and Y is independently selected from —CH 2 —, —NH—, —O— and —S—.
  • each Y is selected from —CH 2 —, —NH—, —O— and —S—.
  • Hydrophill refers to the radical —OH.
  • Oxo refers to the radical ⁇ O.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • “Sulfo’ or ‘sulfonic acid’ refers to a radical such as —SO 3 H.
  • Thiol refers to the group —SH.
  • substituted with one or more refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • ‘Solvate’ encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylaxis is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • allergic airway disease e.g. asthma, rhinitis
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases
  • autoinflammatory diseases(s) refers to the group of diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease.
  • Cryopyrin-Associated Periodic Syndromes Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease.
  • CAPS Cryopyrin-Associated Periodic Syndromes
  • FMF Familial Mediterranean Fever
  • TRAPS Tumor necrosis factor receptor-associated periodic syndrome
  • Behçets Behçets
  • SJIA Systemic-Onset Juvenile Idiopathic Arth
  • autoimmune disease(s) refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • COPD chronic or inveterate asthma
  • bronchitis including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • autoimmune hepatitis primary sclerosing cholangitis, and primary biliary cirrhosis
  • Sjögren's syndrome multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • proliferative disease(s) refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis.
  • cancer e.g. uterine leiomyosarcoma or prostate cancer
  • myeloproliferative disorders e.g. polycythemia vera, essential thrombocytosis and myelofibrosis
  • leukemia e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia
  • multiple myeloma psoriasis
  • restenosis scleroderma or fibrosis
  • cancer refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer,
  • cancer refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, reti
  • leukemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • fibrotic disease(s) refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • systemic sclerosis renal fibrosis
  • cutaneous fibrosis fibrotic diseases
  • tissue rejection refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • pancreatic islets e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • diseases involving impairment of cartilage turnover includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • cartilage malformation(s) includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
  • osteoporosis including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis
  • osteoporosis caused through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinaemia, excess glucocorticoid, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia.
  • disease(s) associated with hypersecretion of IL-6 includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • disease(s) associated with hypersecretion of of of TNF ⁇ , interferons, IL-12 and/or IL-23 includes conditions such as systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the term ‘respiratory disease(s)’ refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves.
  • respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • asthma adult respiratory distress syndrome and allergic (extrinsic) asthma
  • non-allergic (intrinsic) asthma acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset
  • endocrine and/or metabolic disease(s) refers to the group of conditions involving the body's over- or under-production of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins.
  • Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others.
  • Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • a particular example of metabolic disorders is obesity and/or type II diabetes.
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both.
  • cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis.
  • dermatological disorders include proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria.
  • proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria.
  • abnormal angiogenesis associated disease(s) refers to diseases caused by the dysregulation of the processes mediating angiogenesis.
  • abnormal angiogenesis associated disease refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.
  • Compound(s) of the invention are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the C 1-8 alkyl, C 2-s alkenyl, C 6-10 optionally substituted aryl, and (C 6-10 aryl)-(C 1-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an “isotopically enriched variant form”).
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulphur-35 ( 35 S), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 (
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e 2 H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases.
  • the compounds of the invention may be SIK inhibitors, more particularly SIK1, SIK2 and/or SIK3 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compounds of the invention.
  • inflammatory diseases autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL
  • X is N or CH
  • Y is N or CR 2b ;
  • the compound of the invention is according to Formula I, wherein Z is
  • the compound of the invention is according to Formula I, wherein X is N.
  • the compound of the invention is according to Formula I, wherein X is CH.
  • the compound of the invention is according to Formula I, wherein R 2a is halo.
  • R 2a is F, Cl, or Br. In a more particular embodiment, R 2a is F.
  • the compound of the invention is according to Formula I, wherein R 2a is C 1-4 alkyl.
  • R 2a is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 2a is —CH 3 .
  • the compound of the invention is according to Formula I, wherein R 2a is C 1-4 alkoxy.
  • R 2a is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2a is —O—CH 3 or —O—CH 2 CH 3 .
  • R 2a is —O—CH 3 .
  • the compound of the invention is according to Formula I, wherein R 2a is C 1-4 alkoxy substituted with one or more independently selected halo or C 1-4 alkoxy.
  • R 2a is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or C 1-4 alkoxy.
  • R 2a is C 1-4 alkoxy substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2a is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2a is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2a is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2a is —O—CH 3 , substituted with one, two, or three independently selected halo.
  • R 2a is —O—CH 2 CH 3 , substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2a is —O—CHF 2 or —O—CH 2 CH 2 —O—CH 2 CH 3 .
  • the compound of the invention is according to Formula I, wherein R 2a is —NR 6a R 6b , and R 6a and R 6b are independently selected from H and C 1-4 alkyl.
  • R 6a and R 6b are both H.
  • one of R 6a and R 6b is H, and the other is C 1-4 alkyl.
  • R 6a and R 6b are both C 1-4 alkyl.
  • one of R 6a and R 6b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 6a and R 6b are independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • one of R 6a and R 6b is H, and the other is —CH 3 .
  • the compound of the invention is according to Formula I, wherein Z is —NR 3b — wherein the N atom and R 2a together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds, and R 3b is as previously described.
  • Z is —NR 3b —, wherein the N atom and R 2a together with the atoms onto which they are attached form a fused 3-pyrroline, 1,2-dihydropyridine, or 1,2,3,6-tetrahydropyridine.
  • Z is —NR 3b —, wherein the N atom and R 2a together with the atoms onto which they are attached form a fused 1,2,3,6-tetrahydropyridine.
  • the compound of the invention is according to Formula IIa, IIb, or IIc:
  • R 1 , R 3b , and Y are as described above.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b is H.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b is C 3-7 cycloalkyl.
  • R 3b is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 3b is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b is C 1-6 alkyl.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 .
  • R 3b is —CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b is C 1-6 alkyl substituted with one or more independently selected halo or —CN.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or —CN.
  • R 3b is C 1-6 alkyl substituted with one, two, or three independently selected halo or —CN.
  • R 3b is C 1-6 alkyl substituted with one or more independently selected F, Cl, or —CN.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected halo or —CN.
  • R 3b is C 1-6 alkyl substituted with one, two, or three independently selected F, Cl, or —CN.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more independently selected F, Cl, or —CN.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected F, Cl, or —CN.
  • R 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more F or —CN.
  • R 3b is C 1-6 alkyl substituted with one, two, or three independently selected F or —CN.
  • R 3b is —CH 2 CH 3 substituted with one, two, or three F.
  • R 3b is —CH 2 —CN.
  • R 3b is —CH 2 CF 3 .
  • the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.
  • Z is azetidinyl.
  • the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15 groups.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or more independently selected R 15 groups.
  • Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one, two, or three independently selected R 15 groups.
  • Z is azetidinyl substituted with one or more independently selected R 15 groups.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 15 groups.
  • Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or two independently selected R 15 group.
  • Z is azetidinyl substituted with one, two, or three independently selected R 15 groups.
  • Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or two independently selected R 15 groups. In a most particular embodiment, Z is azetidinyl substituted with one or two independently selected R 15 groups.
  • the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15 groups, and R 15 is —OH, —CN, or C 1-4 alkyl.
  • R 15 is —OH, —CN, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 15 is —OH or —CN.
  • the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15 groups, and R 15 is C 1-4 alkyl substituted with one or more independently selected halo or —CN.
  • R 15 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or —CN.
  • R 15 is C 1-4 alkyl substituted with one, two, or three independently selected halo or —CN.
  • R 15 is C 1-4 alkyl substituted with one or more F, Cl, Br, or —CN.
  • R 15 is —CH 3 substituted with one or more independently selected halo or —CN.
  • R 15 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or —CN.
  • R 15 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each of which is substituted with one or more independently selected F, Cl, Br, or —CN.
  • R 15 is C 1-4 alkyl substituted with one, two, or three independently selected F, Cl, Br, or —CN. In a further more particular embodiment, R 15 is —CH 3 substituted with one, two, or three independently selected halo or —CN. In another further more particular embodiment, R 15 is —CH 3 substituted with one or more, two, or three independently selected F, Cl, Br, or —CN. In a most particular embodiment, R 15 is —CH 3 substituted with one, two, or three independently selected F or —CN.
  • the compound of the invention is according to Formula I, wherein Z is —NHR 3a , and R 3a is C 1-6 alkyl.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 )CH 2 CH 3 , or —CH(CH 3 )CH(CH 3 ) 2 .
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —CH 2 CH(CH 3 ) 2 . In a most particular embodiment, R 3a is —CH 2 CH 3 .
  • the compound of the invention is according to Formula I, wherein Z is —NHR 3a and R 3a is C 1-6 alkyl substituted with one or more independently selected halo or —CN.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or —CN.
  • R 3a is C 1-6 alkyl substituted with one, two, or three independently selected halo or —CN.
  • R 3a is C 1-6 alkyl substituted with one or more independently selected F, Cl, or —CN.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected halo or —CN.
  • R 3a is C 1-6 alkyl substituted with one, two, or three independently selected F, Cl, or —CN.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more independently selected F, Cl, or —CN.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected F, Cl, or —CN.
  • R 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each of which is substituted with one or more F or —CN.
  • R 3a is C 1-6 alkyl substituted with one, two, or three independently selected F or —CN.
  • R 3a is —CH 2 CH 3 substituted with one, two, or three F.
  • R 3a is —CH 2 —CN.
  • R 3a is —CH 2 CF 3 .
  • the compound of the invention is according to Formula I, wherein Z is —NHR 3a and R 3a is C 3-7 cycloalkyl.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 3a is cyclopropyl.
  • the compound of the invention is according to Formula I, wherein Z is —NHR 3a and R 3a is C 3-7 cycloalkyl substituted with one or more independently selected halo or —OH.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected halo or —OH.
  • R 3a is C 3-7 cycloalkyl substituted with one, two, or three independently selected halo or —OH.
  • R 3a is C 3-7 cycloalkyl substituted with one or more independently selected F, Cl, or —OH.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected halo or —OH.
  • R 3a is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, Cl, or —OH.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected F, Cl, or —OH.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected F, Cl, or —OH.
  • R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more F or —OH.
  • R 3a is C 3-7 cycloalkyl substituted with one, two, or three independently selected F or —OH.
  • R 3a is
  • R 3a is
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is N.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b and R 2b is halo.
  • R 2b is F, Cl, or Br.
  • R 2b is F.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b and R 2b is C 1-4 alkyl.
  • R 2b is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 2b is —CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b and R 2b is C 1-4 alkoxy.
  • R 2b is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2b is —O—CH 3 or —O—CH 2 CH 3 .
  • R 2b is —O—CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b and R 2b is C 1-4 alkoxy substituted with one or more independently selected halo or C 1-4 alkoxy.
  • R 2b is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or C 1-4 alkoxy.
  • R 2b is C 1-4 alkoxy substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2b is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2b is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2b is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 2b is —O—CH 3 , substituted with one, two, or three independently selected halo.
  • R 2b is —O—CH 2 CH 3 , substituted with one, two, or three independently selected halo or C 1-4 alkoxy.
  • R 2b is —O—CHF 2 or —O—CH 2 CH 2 —O—CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b , R 2b is —NR 6a R 6b , and R 6a and R 6b are independently selected from H and C 1-4 alkyl.
  • R 6a and R 6b are both H.
  • one of R 6a and R 6b is H, and the other is C 1-4 alkyl.
  • R 6a and R 6b are both C 1-4 alkyl.
  • one of R 6a and R 6b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 6a and R 6b are —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • one of R 6a and R 6b is H, and the other is —CH 3 .
  • the compound of the invention is according to Formula IIIa, IIIb, or IIIc:
  • R 1 is as described above.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is C 1-8 alkyl.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , or —CH 2 CH 2 CH 2 CH(CH 3 ) 2 .
  • R 1 is —CH 3 , —CH 2 CH 3 , or —CH 2 C(CH 3 ) 3 .
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is C 1-8 alkyl substituted with one or more independently selected R 4 groups.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH
  • R 1 is C 1 _s alkyl substituted with one, two, or three independently selected R 4 groups.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , or —CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R 4 groups.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 2 CH 3 ,
  • R 1 is C 1-8 alkyl substituted with one R 4 group.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , or —CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R 4 groups.
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 2 CH 3 ,
  • R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , or —CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one R 4 group.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is phenyl.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is C 3-8 monocyclic or bridged polycyclic cycloalkyl.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.
  • R 1 is cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptanyl.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one or more independently selected R 15 groups.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one or more independently selected R groups.
  • R 1 is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one, two, or three independently selected R 5 groups.
  • R 1 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected R 5 groups.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one, two, or three independently selected R 15 groups.
  • R 1 is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one R 5 group.
  • R 1 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected R 5 groups.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one R 5 group.
  • R 1 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one R 5 group.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspir
  • R 1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, or 8-azabicyclo[3.2.1]octanyl.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspir
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected C 1-4 alkyl optionally substituted with one or more independently selected —CN or —C( ⁇ O)—C 1-4 alkoxy.
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspir
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxas
  • R 1 is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl optionally substituted with one or more independently selected —CN or —C( ⁇ O)—C 1-4 alkoxy.
  • R 1 is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each of which is optionally substituted with one, two, or three independently selected —CN, —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , or —C( ⁇ O)—O—CH(CH 3 ) 2 .
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxas
  • R 1 is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one —CH 3 , —CH 2 —CH 2 —CN, or —CH 2 —C( ⁇ O)—O—CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected C 1-4 alkyl.
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspir
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxas
  • R 1 is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl.
  • R 1 is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one, two, or three independently selected —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxas
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1 is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R 1 is pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R 1 is pyridinyl.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R 5 is halo or —CN.
  • R 5 is F, Cl, Br, or —CN.
  • R 5 is F or —CN.
  • the compound of the invention is according to any one of Formulae I-IIIc, wherein R is —NR 13a R 13b , and each R 13a and R 13b are as previously described.
  • R 13a and R 13b are both H.
  • one of R 13a and R 13b is H, and the other is C 1-4 alkyl.
  • R 13a and R 13b are both C 1-4 alkyl.
  • one of R 13a and R 13b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • each R 13a and R 13b is independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R is —NH—CH 3 .
  • the compound of the invention is according to Formula IVa, IVb, IVc, IVd, IVe, or IVf:
  • R 4 is as described above.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is halo, —OH, —CN, phenyl, or —C( ⁇ O)OH.
  • R 4 is F, Cl, Br, —OH, —CN, phenyl, or —C( ⁇ O)OH.
  • R 4 is F, —OH, —CN, phenyl, or —C( ⁇ O)OH.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is halo, —OH, —CN, or phenyl.
  • R 4 is F, Cl, Br, —OH, —CN, or phenyl.
  • R 4 is F, —OH, —CN, or phenyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —O—C( ⁇ O)—C 1-4 alkyl.
  • R 4 is —O—C( ⁇ O)—CH 3 , —O—C( ⁇ O)—CH 2 CH 3 , or —O—C( ⁇ O)—CH(CH 3 ) 2 .
  • R 4 is —O—C( ⁇ O)—CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —O—S( ⁇ O) 2 —C 1-4 alkyl.
  • R 4 is —O—S( ⁇ O) 2 —CH 3 , —O—S( ⁇ O) 2 —CH 2 CH 3 , or —O—S( ⁇ O) 2 —CH(CH 3 ) 2 .
  • R 4 is —O—S( ⁇ O) 2 —CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 1-4 alkoxy.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 4 is —O—CH 3 or —O—CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 1-4 alkoxy substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is C 1-4 alkoxy substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is C 1-4 alkoxy substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is —O—CH 2 CH 3 substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one —CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 1-4 alkoxy substituted with one or more independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is C 1-4 alkoxy substituted with one, two or three independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is C 1-4 alkoxy substituted with one or more independently selected —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one or more independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one, two or three independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more independently selected —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is C 1-4 alkoxy substituted with one, two or three independently selected —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one or more independently selected —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one, two, or three independently selected —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 2 CH 3 substituted with one or more independently selected —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one or more —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is C 1-4 alkoxy substituted with one, two, or three —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one —OH, C 1-4 alkoxy, or —NR 7a R 7b , wherein each R 7a and R 7b is independently selected from H and C 1-4 alkyl.
  • R 4 is —O—CH 2 CH 3 substituted with one, two, or three —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2, —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one or more —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one, two, or three —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one —OH, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —NH—CH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )—CH 2 CH 3 , —N(CH 3 )—CH(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 3 )—CH(CH 3 ) 2 , or —N(CH(CH 3 ) 2 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one, two, or three —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with one —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • R 4 is —O—CH 2 CH 3 substituted with one —OH, —O—CH 3 , or —N(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 3-7 cycloalkyl.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 3-7 cycloalkyl substituted with one or more independently selected halo, —C( ⁇ O)—C 1-4 alkoxy, —NR 8a R 8b , or C 1-4 alkyl optionally substituted with one or more independently selected —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected halo, —C( ⁇ O)—C 1-4 alkoxy, —NR 8a R 8b , or C 1-4 alkyl optionally substituted with one or more independently selected —NR 9a R 9b .
  • R 4 is C 3-7 cycloalkyl substituted with one, two, or three independently selected halo, —C( ⁇ O)—C 1-4 alkoxy, —NR 8a R 8b , or C 1-4 alkyl optionally substituted with one or more independently selected —NR 9a R 9b .
  • R 4 is C 3-7 cycloalkyl substituted with one or more independently selected F, Cl, Br, —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , —C( ⁇ O)—O—CH(CH 3 ) 2 , —NR 8a R 8b , —CH 3 optionally substituted with one —NR 9a R 9b , —CH 2 CH 3 optionally substituted with one —NR 9a R 9b , or —CH(CH 3 ) 2 optionally substituted with one —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected halo, —C( ⁇ O)—C 1-4 alkoxy, —NR 8a R 8b , or C 1-4 alkyl optionally substituted with one or more independently selected —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, Cl, Br, —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , —C( ⁇ O)—O—CH(CH 3 ) 2 , —NR 8a R 8b , —CH 3 optionally substituted with one —NR 9a R 9b , —CH 2 CH 3 optionally substituted with one —NR 9a R 9b , or —CH(CH 3 ) 2 optionally substituted with one —NR 9a R 9b .
  • R 4 is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, Cl, Br, —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , —C( ⁇ O)—O—CH(CH 3 ) 2 , —NR 8a R 8b , —CH 3 optionally substituted with one —NR 9a R 9b , —CH 2 CH 3 optionally substituted with one —NR 9a R 9b , or —CH(CH 3 ) 2 optionally substituted with one —NR 9a R 9b .
  • R 4 is C 3-7 cycloalkyl substituted with one or more independently selected F, —C( ⁇ O)—O—CH 3 , —NR 8a R 8b , —CH 3 , or —CH 2 —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , —C( ⁇ O)—O—CH(CH 3 ) 2 , —NR 8a R 8b , —CH 3 optionally substituted with one —NR 9a R 9b , —CH 2 CH 3 optionally substituted with one —NR 9a R 9b , or —CH(CH 3 ) 2 optionally substituted with one —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, —C( ⁇ O)—O—CH 3 , —NR 8a R 8b , —CH 3 , or —CH 2 —NR 9a R 9b .
  • R 4 is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, —C( ⁇ O)—O—CH 3 , —NR 8a R 8b , —CH 3 , or —CH 2 —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected F, —C( ⁇ O)—O—CH 3 , —NR 8a R 8b , —CH 3 , or —CH 2 —NR 9a R 9b .
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three F.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one —C( ⁇ O)—O—CH 3 , —NR 8a R 8b , —CH 3 , or —CH 2 —NR 9a R 9b .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 3-7 cycloalkyl substituted with —NR 8a R 8b , and R 8a and R 8b are as previously described.
  • R 8a and R 8b are both H.
  • one of R 8a and R 8b is H, and the other is C 1-4 alkyl.
  • R 8a and R 8b are both C 1-4 alkyl.
  • one of R 8a and R 8b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 8a and R 8b are independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is C 3-7 cycloalkyl substituted with one or more independently selected C 1-4 alkyl substituted with one or more independently selected —NR 9a R 9b , and R 9a and R 9b are as previously described.
  • R 9a and R 9b are both H.
  • one of R 9a and R 9b is H, and the other is C 1-4 alkyl.
  • R 9a and R 9b are both C 1-4 alkyl.
  • one of R 9a and R 9b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 9a and R 9b are independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 4 is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine.
  • R 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine.
  • R 4 is 1H,2H,3H,4H-pyrrolo[1,2-a]pyrazinyl, 5H,6H,7H,8H-imidazo[1,2-a]pyrazinyl, 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, or 5H,6H,7H,8H-pyrido[4,3-d]pyrimidinyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl.
  • R 4 is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with one, two, or three independently selected —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with one, two, or three independently selected —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is piperidinyl fused to an imidazole substituted with one —CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 4 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.
  • R 4 is thiazolyl, oxazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 4 is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl.
  • R 4 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two, or three independently selected —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 4 is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one or two independently selected —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or cyclopropyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-o
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2,8-dioxa-5-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexany
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-thia-1-azaspiro[3.3]
  • R 4 is 4-11 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, each of which is substituted with one or more independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-thia-1-azaspiro[3.3]
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, each of which is substituted with one, two, or three independently selected R 10 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexany
  • R 4 is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, each of which is substituted with one or more independently selected R 10 .
  • R 4 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]hept
  • R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 10 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 , and R 10 is as previously described.
  • R 10 is —OH, phenyl, ⁇ NH, halo, oxo, —CN, —C( ⁇ O)H, —C( ⁇ O)NH 2 , —C( ⁇ O)OH, —NR 14a R 14b , C 1-4 alkyl optionally substituted with one or more independently selected halo, —CN, —OH, —C( ⁇ O)—C 1-4 alkoxy, or C 1-4 alkoxy, C 3-7 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, —C( ⁇ O)—C 1-4 alkyl, —S( ⁇ O) 2 —C 1-4 alkyl, or —C( ⁇ O)—C 1-6 alkoxy.
  • R 10 is —OH, phenyl, ⁇ NH, F, Cl, Br, oxo, —CN, —C( ⁇ O)H, —C( ⁇ O)NH 2 , —C( ⁇ O)OH, —NR 14a R 14b , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CN, —CH 2 —CH 2 —CN, —CH(CH 3 )—CN, —C(CH 3 ) 2 —CN, —CH(CH 3 )—CH 2 —CN, —CH 2 —C(CH 3 ) 2 —CN, —CH 2 —OH, —CH 2 —CH 2 —OH, —CH(CH 3 )—OH, —C(CH 3 ) 2 —OH, —C(CH
  • R 10 is —OH, phenyl, ⁇ NH, F, oxo, —CN, —C( ⁇ O)H, —NR 14a R 14b , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CN, —CH 2 —CH 2 —CN, —CH 2 —OH, —CH 2 —CH 2 —OH, —CH 2 —C(CH 3 ) 2 —OH, —CH 2 —C( ⁇ O)—O—CH 2 —CH 3 , —CH 2 —O—CH 3 , cyclopropyl, oxetanyl, —C( ⁇ O)—CH 3 , —S( ⁇ O) 2 —CH 3 , —C( ⁇ O)—O—CH 3 , —C(CH 3 , —
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 , and R 10 is as previously described.
  • R 10 is halo, oxo, —CN, —C( ⁇ O)H, —NR 14a R 14b , C 1-4 alkyl optionally substituted with one or more independently selected halo or C 1-4 alkoxy, C 3-7 cycloalkyl, —C( ⁇ O)—C 1-4 alkyl, —S( ⁇ O) 2 —C 1-4 alkyl, or —C( ⁇ O)—C 1-6 alkoxy.
  • R 10 is F, Cl, Br, oxo, —CN, —C( ⁇ O)H, —NR 14a R 14b , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —O—CH 3 , —CH 2 CH 2 —O—CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C( ⁇ O)—CH 3 , —C( ⁇ O)—CH 2 CH 3 , —C( ⁇ O)—CH(CH 3 ) 2 , —S( ⁇ O) 2 —CH 3 , —S( ⁇ O) 2 —CH 3 , —S( ⁇ O) 2 —CH 3 , —S( ⁇ O) 2 —CH 2 CH 3 , —
  • R 10 is F, oxo, —CN, —C( ⁇ O)H, —NR 14a R 14b , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —O—CH 3 , cyclopropyl, —C( ⁇ O)—CH 3 , —S( ⁇ O) 2 —CH 3 , —C( ⁇ O)—O—CH 3 , or —C( ⁇ O)—O—C(CH 3 ) 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 , R 10 is —NR 14a R 14b , and R 14a and R 14b are as previously described.
  • R 14a and R 14b are both H.
  • one of R 14a and R 14b is H, and the other is C 1-4 alkyl or —S( ⁇ O) 2 —C 1-4 alkyl.
  • R 14a and R 14b are independently C 1-4 alkyl or —S( ⁇ O) 2 —C 1-4 alkyl.
  • one of R 14a and R 14b is H, and the other is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or —S( ⁇ O) 2 —CH 3 .
  • R 14a and R 14b are independently —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or —S( ⁇ O) 2 —CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10 , R 10 is —NR 14a R 14b , and R 14a and R 14b are as previously described.
  • R 14a and R 14b are both H.
  • one of R 14a and R 14b is H, and the other is C 1-4 alkyl.
  • R 14a and R 14b are both C 1-4 alkyl.
  • one of R 14a and R 14b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 14a and R 14b are independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , and R 11a and R 11b are as previously described.
  • R 11a is H.
  • R 11a is C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, —CN, or C 1-4 alkoxy.
  • R 11a is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or —CH 2 CHF 2 .
  • R 11a is —CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is H or phenyl. In a most particular embodiment, R 4 is —NH 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is C 1-4 alkyl.
  • R 11b is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 4 is —NH—CH 3 , —N(CH 3 ) 2 , —NH—CH 2 CH 3 , —N(CH 2 CH 3 ) 2 , —N(CH(CH 3 ) 2 ) 2 , or —N(CH 3 )—CH 2 CHF 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is C 1-4 alkyl substituted with one or more independently selected halo, —OH, —CN, or C 1-4 alkoxy.
  • R 11b is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo, —OH, —CN, or C 1-4 alkoxy.
  • R 11b is C 1-4 alkyl substituted with one, two, or three independently selected halo, —OH, —CN, or C 1-4 alkoxy.
  • R 11b is C 1-4 alkyl substituted with one or more independently selected halo, —OH, —CN, —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 .
  • R 11b is —CH 3 , or —CH 2 CH 3 , each of which is substituted with one F, —OH, —CN, or —O—CH 3 .
  • R 11b is —CH 2 —CN, —CH 2 CH 2 —OH, or —CH 2 CH 2 —O—CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is C 3-7 cycloalkyl.
  • R 11b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 11b is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is —C( ⁇ O)—C 1-4 alkoxy.
  • R 11b is —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , or —C( ⁇ O)—O—CH(CH 3 ) 2 .
  • R 11b is —C( ⁇ O)—O—CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NR 11a R 11b , R 11a is as previously described, and R 11b is —C( ⁇ O)—C 1-4 alkyl.
  • R 11b is —C( ⁇ O)—CH 3 , —C( ⁇ O)—CH 2 CH 3 , or —C( ⁇ O)—CH(CH 3 ) 2 .
  • R 11b is —C( ⁇ O)—CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NRu 11a R 11b , R 11a is as previously described, and R 11b is —C( ⁇ O)—C 1-4 alkyl substituted with one or more independently selected halo.
  • R 11b is —C( ⁇ O)—CH 3 , —C( ⁇ O)—CH 2 CH 3 , or —C( ⁇ O)—CH(CH 3 ) 2 , each of which is substituted with one, two, or three F, Cl, or Br.
  • R 11b is —C( ⁇ O)—CH 3 substituted with one, two, or three F.
  • R 11b is —C( ⁇ O)—CHF 2 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —NRu 11a R 11b , R 11a is as previously described, and R 11b is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S.
  • R 11b is pyrrolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, furazanyl, thiadiazolyl, oxadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.
  • R 11b is pyridinyl, pyridazinyl, or pyrimidinyl.
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —C( ⁇ O)—C 1-4 alkoxy.
  • R 4 is —C( ⁇ O)—O—CH 3 , —C( ⁇ O)—O—CH 2 CH 3 , or —C( ⁇ O)—O—CH(CH 3 ) 2 .
  • R 4 is —C( ⁇ O)—O—CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVf, wherein R 4 is —C( ⁇ O)—NR 12a R 12b , and each R 12a and R 12b are as previously described.
  • R 12a and R 12b are both H.
  • one of R 12a and R 12b is H, and the other is C 1-4 alkyl.
  • R 12a and R 12b are both C 1-4 alkyl.
  • one of R 12a and R 12b is H, and the other is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • each R 12a and R 12b is independently —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
  • R 12a and R 12b are —CH 3 .
  • the compound of the invention is according to Formula I, wherein the compound is selected from:
  • the compound of the invention is according to Formula I, wherein the compound is selected from:
  • the compound of the invention according to Formula I is selected from:
  • the compound of the invention is according to Formula I, wherein the compound is 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.
  • the compound of the invention is according to Formula I, wherein the compound is not 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.
  • the compound of the invention is according to Formula I, wherein the compound is 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.
  • the compound of the invention is according to Formula I, wherein the compound is not 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.
  • a compound of the invention is not an isotopic variant.
  • a compound of the invention according to any one of the embodiments herein described is present as the free base.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds of the invention.
  • X is N or CH
  • Y is N or CR 2b ;
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences. (Remington 1985)
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • a compound of the invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75° C. and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a inflammatory diseases treatment agent.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoinflammatory diseases.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of autoinflammatory diseases.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoinflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a autoinflammatory diseases treatment agent.
  • autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an autoimmune diseases treatment agent.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a proliferative diseases treatment agent.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a fibrotic diseases treatment agent.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of transplantation rejection.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of transplantation rejection.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with transplantation rejection, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a transplantation rejection treatment agent.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, ps
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases involving impairment of cartilage turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases involving impairment of cartilage turnover treatment agent.
  • diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis,
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of congenital cartilage malformation.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of congenital cartilage malformation.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with congenital cartilage malformation, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a congenital cartilage malformation treatment agent.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases involving impairment of bone turnover.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases involving impairment of bone turnover.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases involving impairment of bone turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases involving impairment of bone turnover treatment agent.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of IL-6.
  • diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases associated with hypersecretion of IL-6.
  • diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases associated with hypersecretion of IL-6, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases associated with hypersecretion of IL-6 treatment agent.
  • diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23.
  • diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23.
  • diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 treatment agent.
  • diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a respiratory diseases treatment agent.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with endocrine and/or metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a endocrine and/or metabolic diseases treatment agent.
  • endocrine and/or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and/or type II diabetes.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a cardiovascular diseases treatment agent.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of dermatological diseases.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of dermatological diseases.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with dermatological diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a dermatological diseases treatment agent.
  • dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of abnormal angiogenesis associated diseases.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of abnormal angiogenesis associated diseases.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with abnormal angiogenesis associated diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a abnormal angiogenesis associated diseases treatment agent.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation
  • agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).
  • analgesics for example but without limitation methotrexate, leflunomide, sulfasalazin
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders
  • therapeutic agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
  • the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases
  • agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g.
  • anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies Atgam® and Thymoglobuline®
  • cyclosporin tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN- ⁇ ), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin.
  • tacrolimus rapamycin (sirolimus)
  • interferons e.g. IFN- ⁇
  • TNF binding proteins e.g. infliximab, etanercept, or adalimumab
  • mycophenolate fingolimod and myriocin.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection
  • agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)).
  • calcineurin inhibitors e.g. cyclosporin or tacrolimus (FK506)
  • mTOR inhibitors e.g. sirol
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD
  • particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled), long-acting ⁇ 2-agonists (e.g.
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. cetirizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
  • bronchodilators e.g. fluticasone/salmeterol, budesonide/formote
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol orterbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration nebulized salbutamol orterbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
  • glucocorticoids e.g. prednisone, budesonide
  • immunomodulatory agents e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE
  • particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
  • DMARDs Disease-modifying antirheumatic drugs
  • antimalarials e.g. plaquen
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis
  • particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort®), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologics such as Amevive®, Enbrel®, Humira®, Remicade
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction
  • therapeutic agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti-leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
  • antihistamines e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine
  • glucocorticoids e.g. prednisone, betamethasone, beclomethasone, dexamethasone
  • epinephrine e
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person.
  • the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential.
  • the agents may be administered in different formulations and at different times.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • 1 H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Avance 300 NMR spectrometer (300 MHz). Chemical shifts ( ⁇ ) for 1 H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane ( ⁇ 0.00) or the appropriate residual solvent peak, i.e. CHCl 3 ( ⁇ 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (in) and broad (br).
  • Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer.
  • the methods are using ACN/H 2 O or MeOH/water gradients with either 0.1% formic acid in both mobile phases, 0.05% NH 3 in both mobile phases, or 10 mM NH 4 HCO 3 in H 2 O (adjusted to pH 10 with ammonia).
  • Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBRIDGE BEH C18 OBD 30 mm ID ⁇ 100/150 mm L columns and ACN/H 2 O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H 2 O, or 10 mM NH 4 HCO 3 in H 2 O (adjusted to pH 10 with ammonia).
  • Microwave heating is performed with a Biotage® Initiator.
  • BrettPhos 2-(Dicyclohexylphosphino)3,6- dimethoxy-2′,4′,6′-triisopropyl- 1,1′-biphenyl br broad singlet calcd calculated d doublet DCM dichloromethane dd doublet of doublets DIPEA N,N-diisopropylethylamine DMAC dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DPPF 1,1′- bis(diphenylphosphino)ferrocene Et 3 N triethylamine Et 2 O diethyl ether EtOAc ethyl acetate EtOH
  • Alternative work-up 1 the reaction mixture is concentrated to dryness, the residue is taken up in EtOAc and filtered. Then, the filtrate is concentrated.
  • Alternative work-up 2 the reaction mixture is concentrated, the residue is taken up in EtOAc and 2N aq. NaOH. The aqueous phase is extracted with EtOAc and the combined organic layers are concentrated.
  • Alternative work-up 3 the reaction mixture is quenched with a sat. aq. NaHCO 3 solution and extracted with EtOAc. The combined organic layers are directly evaporated or are dried on a desiccant, filtered and evaporated, or are washed with brine, passed through a phase separator, and concentrated.
  • Alternative work-up 4 the reaction mixture is quenched with 2N aq.
  • the obtained residues are purified by chromatography on silica gel or by preparative HPLC or by a combination of both purification methods to afford the expected compound.
  • the imidazopyridine derivative (1 eq.), the bromo derivative (0.7 to 1.5 eq.) and KOAc (2 to 3 eq.) are suspended in dry DMAC, the mixture is degassed with N 2 before Pd(dppf)Cl 2 .DCM adduct (CAS #95464-05-4, 0.03 to 0.1 eq.) is added, or all the reagents are suspended in dry and degassed DMAC, or all the reagents are suspended in dry DMAC.
  • the mixture is stirred at 105-120° C. for 1 h to 20 h.
  • the reaction medium is concentrated, or is diluted or not with EtOAc, filtered over Celite® and the filtrate concentrated in vacuo.
  • the crude residue is purified by flash chromatography on silica gel or preparative HPLC to afford the expected product.
  • the reaction mixture is cooled to RT, concentrated in vacuo and the crude material is hydrolyzed with a sat. aq. NaHCO 3 solution.
  • the aqueous layer is extracted with EtOAc.
  • the combined organic layers are passed through a phase separator and concentrated under reduced pressure.
  • the residue is purified by chromatography on silica gel (eluting with 0 to 80% EtOAc in DCM) to afford Int 29.
  • a solution of the protected aldehyde (1 eq.) in a DCM/TFA 1/1 mixture is stirred at RT for 4 to 5 h before being concentrated.
  • the residue is taken up in toluene and the solvent is evaporated to dryness.
  • the crude residue is then dissolved in DCM and the amine (1.5 eq.) and NaBH(OAc) 3 (CAS #56553-60-7; 1.5 eq.) are added.
  • Et 3 N (1.5 eq.) can optionally be added to the mixture.
  • the reaction mixture is then stirred at RT for 2 h to 20 h.
  • the reaction medium is either concentrated or quenched with aq. NaOH (1N or 2N aq. solution), extracted with DCM and passed through a phase separator.
  • the crude residue is purified by flash chromatography on silica gel or by preparative HPLC to afford the expected compound.
  • the reaction mixture is stirred at RT overnight and then hydrolysed with 1N aq. NaOH.
  • the aqueous phase is extracted with DCM and passed through a phase separator.
  • the filtrate is concentrated and the crude residue is purified by flash chromatography on a Biotage® SNAP KP-NH cartridge (eluting with a gradient of AcOEt 0 to 100% in heptane then a gradient of MeOH 0 to 4% in DCM) to afford the expected compound Cpd 257, and Cpd 258 as a by-product of the reaction.
  • the epoxide derivative is dissolved in DMSO, then water or ACN is added followed by the amine derivative (1.2 to 5.eq.) and optionally, Et 3 N (5 eq.) when the amine derivative is a salt.
  • the reaction mixture is stirred at RT for 18 to 72 h and then diluted with EtOAc. Water and a sat. NaHCO 3 aq. solution are added and extracted with DCM. Purification by flash chromatography on silica gel affords the expected product.
  • Int 92 (250 mg, 0.561 mmol, 1 eq.) is dissolved in DMSO (10 mL) and water (10 mL) is added followed by morpholine (CAS #110-91-8; 242 ⁇ L, 2.81 mmol, 5 eq.). The reaction mixture is stirred at RT overnight. The reaction mixture is diluted with EtOAc and transferred to a separation funnel. Water and a sat. NaHCO 3 aq. solution are added and extracted with EtOAc. The organic layers are combined, dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on silica gel (eluting with a gradient DCM/(DCM/MeOH/NH 3 in water 90/9.5/0.5) 100/0 to 20/80) to afford Cpd 330.
  • Int 92 (25 mg, 0.056 mmol, 1 eq.) is dissolved in DMSO (0.5 mL) and water (1 mL) is added followed by piperidine (CAS #110-89-4; 6.65 ⁇ L, 0.067 mmol, 1.2 eq.). The reaction mixture is stirred at RT for 48 h. Another portion of piperidine (6.65 ⁇ L, 0.067 mmol, 1.2 eq.) is added. The reaction mixture is stirred at RT for 48 h. Another portion of piperidine (6.65 ⁇ L, 0.067 mmol, 1.2 eq.) is added. The reaction mixture is stirred at RT for 18 h, diluted with DCM and transferred to a separation funnel.
  • a suspension of methyl 4-bromo-2-methoxybenzoate (CAS #139102-34-4; 1 eq.) and hydroxylamine (50 wt % in water; 10 eq.) is heated at 60 to 63° C. for 5 h to 17 h.
  • the reaction mixture is then cooled down to RT.
  • the suspension is filtered and the solid rinsed with water to afford 4-bromo-2-methoxy-benzenecarbohydroxamic.
  • a suspension of methyl 4-bromo-2-methoxybenzoate (CAS #139102-34-4; 4.328 mol, 1 eq.) in hydroxylamine (50 wt % in water, 2859 mL, 10 eq.) is heated at 60 to 63° C. for 14 h.
  • the reaction mixture is cooled down to RT and the suspension is filtered.
  • the solid is washed with water (10 L) and dried at 50° C. in a vacuum oven to afford 4-bromo-N-hydroxy-2-methoxybenzamide.
  • NaOMe (717 g, 13.27 mol, 3.5 eq.) is added over 20 min to a solution of Int 42 (1040 g, 3.79 mol, 1 eq.) in DMSO (5 V, 5200 mL) under N2 atmosphere.
  • the reaction mixture is heated to 100° C. (jacket temperature from 20° C. to 100° C. over 30 min) and stirred at 250 rpm overnight.
  • the reaction mixture is cooled to 20° C. (jacket temperature; ramp from 100° C. to 10° C. in 45 min) and HCl 2 N (5.3 L, 10.6 mol, 0.8 eq./NaOMe) is added in 2 h while maintaining internal temperature below 30° C.
  • the suspension is cooled to 20° C., stirred for 15 min and filtered.
  • the cake is washed with water (2*2 L, 2*2 V).
  • the solid is dried in a vacuum oven at 50° C.
  • the crude solid (1040 g) is dissolved in acetone (3 L, 3 V).
  • the solution is cooled at 15° C. (jacket temperature from 20° C. to 10° C. in 20 min) and water (3 L, 3 V) is progressively added over 30 min. Crystallization starts after adding 800 mL of water.
  • the suspension is cooled down to 15° C. and stirred for 15 min.
  • the suspension is filtered and the cake is washed with water (2*3 L, 2*3 V).
  • the solid is dried in a vacuum oven at 50° C. to afford 4-bromo-N-cyclopropyl-2-hydroxy-6-methoxy-benzamide.
  • potassium hydroxide (10 eq., 243 g) is added to a solution of 4-bromo-N-cyclopropyl-2-hydroxy-6-methoxy-benzamide (1 eq., 124 g) in ACN/water (ACN/H 2 O 1/1, 10 V, 1240 mL).
  • the reaction mixture is cooled to 5° C. (jacket temperature from 20° C. to 0° C. in 40 min).
  • Diethyl (bromodifluoromethyl)phosphonate (CAS #65094-22-6; 2 eq., 154 mL) is added neat over 1 h into the solution at 5° C. (jacket temperature set at 0° C.), while keeping the reaction temperature below 18° C.
  • the reaction mixture is warmed up to 20° C. and stirred at 20° C. for 30 min.
  • the aqueous phase is extracted three times with EtOAc (3*650 mL, 3*5 V).
  • the organic phases are combined and washed once with NaCl 20% (5 V, 650 mL) and concentrated.
  • 6-Bromo-2-(2,2-difluoroethyl)-8-hydroxy-3,4-dihydroisoquinolin-1-one is prepared from Int 6 according to general method F using BBr 3 .
  • Int 16 is prepared from 4-bromo-N-cyclopropyl-2-(difluoromethoxy)-6-hydroxy-benzamide according to general method G.
  • Int 19 is prepared from 4-bromo-2-hydroxy-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide according to general method G.
  • Int 20 is prepared from 6-bromo-8-(methylamino)-3,4-dihydro-2H-isoquinolin-1-one following general method E with 2,2,2-trifluoroethyl trifluoromethanesulfonate.
  • 6-Bromo-2-cyclopropyl-8-hydroxy-3,4-dihydroisoquinolin-1-one is prepared from Int 49 following the general method F using BBr 3 .
  • Methyl 5-bromo-3-hydroxy-pyridine-2-carboxylate (CAS #1242320-57-5; 50 mg, 0.215 mmol), sodium chlorodifluoroacetate (CAS #1895-39-2; 35 mg, 0.26 mmol) and K 2 CO 3 (60 mg, 0.63 mmol) are mixed in ACN (1.5 mL) and the reaction mixture is stirred at reflux for 2 h. The reaction medium is quenched with a sat. aq. NaHCO 3 solution and ice. The mixture is extracted with DCM and then EtOAc. The combined organic layers are dried over Na 2 SO 4 , filtered and concentrated. The crude material is purified by chromatography on silica gel (eluting with EtOAc in heptane) to afford the desired methyl 5-bromo-3-(difluoromethoxy)pyridine-2-carboxylate.
  • reaction mixture is cooled down to 10° C. and additional LiHMDS (LOM in THF, 200 mL, 0.200 mol, 0.085 eq.) is added dropwise in 15 min.
  • the reaction mixture is stirred at 20° C. for 30 min.
  • 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS #6226-25-1; 30 mL, 0.208 mmol, 0.09 eq.) is added in one portion and the reaction mixture is heated from 20° C. to 65° C. in 1 h.
  • the reaction mixture is then cooled down to 10° C. and a 1N HCl aq. solution is added dropwise until pH 1 is reached ( ⁇ 4 L).
  • the suspension is stirred for 1 h at 20° C. and THF is completely evaporated under reduced pressure.
  • the resulting suspension is filtered and the solid is washed twice with water (1.8 L).
  • the solid is suspended in MTBE (2 L) and stirred at RT for 1 h.
  • the suspension is filtered and the solid is washed with heptane (2 L) and dried to afford Int 39.
  • the reaction mixture is then cooled to 25° C. (jacket temperature from 90° C. to 5° C. over 45 min) and HCl 2 N (2.7 L, 5.4 mol, 0.63 eq./NaOH) is added until pH 3 is reached.
  • the temperature is kept below 30° C. during the addition of HCl (addition over 20 min and jacket temperature set at 5° C.).
  • the suspension is stirred at 200 rpm for 2 h while the temperature decreases to 20° C. (jacket temperature set at 5° C.).
  • the suspension is then filtered.
  • the wet cake is washed with water (twice with 2 L, 2*2 V) and the solid is dried on a fritted funnel overnight.
  • the liquid residue is diluted with DCM (453 mL, 5 volumes).
  • Trifluoro ethylamine hydrochloride 54.34 g, 400.95 mmol, 1.05 eq.
  • Et 3 N 117.09 mL, 840.08 mmol, 2.2 eq.
  • the reaction mixture is then stirred under N 2 at RT for 14 h.
  • the suspension is diluted with DCM (1000 mL, 10 volumes).
  • the organic phase is washed with water (500 mL, 5 volumes) and sat. NaHCO 3 (500 mL, 5 volumes).
  • reaction medium is quenched with a sat. aq. NaHCO 3 solution and extracted with EtOAc. The combined organic layers are dried over MgSO 4 , filtered and concentrated. The crude material is purified by chromatography on silica gel (eluting with a gradient of 0 to 60% EtOAc in heptane) twice to afford the expected 6-bromo-2-cyclopropyl-8-fluoro-3,4-dihydroisoquinolin-1-one.
  • Int 49 is prepared from 6-bromo-2-cyclopropyl-8-fluoro-3,4-dihydroisoquinolin-1-one according to general method D using MeONa as reagent.
  • the reaction mixture is concentrated in vacuo and the crude material is purified by chromatography on silica gel (eluting with a gradient of 0 to 5% MeOH in DCM) to afford the expected compound as a mixture with Int 53 (70% Int 52/30% Int 53).
  • 2-hydroxy-6-methyl-N-(2,2,2-trifluoroethyl)benzamide is prepared from 2-methoxy-6-methyl-N-(2,2,2-trifluoroethyl)benzamide according general method G using BCl 3 .
  • 2-hydroxy-6-methyl-N-(2,2,2-trifluoroethyl)benzamide (490 mg, 2.10 mmol) is suspended in a ACN (2.5 mL)/H 2 O (2.5 mL) mixture.
  • KOH (1.18 g, 21.01 mmol) is added portionwise at 0° C.
  • diethyl (bromodifluoromethyl)phosphonate (CAS #65094-22-6; 747 ⁇ L, 4.20 mmol) is added dropwise keeping the temperature below 20° C.
  • the reaction mixture is stirred at 0° C. for 30 min before being warmed up to RT.
  • the aqueous layer is extracted with EtOAc.
  • the combined organic layers are washed with brine, passed through a phase separator and concentrated.
  • the crude material is purified by chromatography on silica gel (eluting with a gradient of 0 to 20% EtOAc in heptane) to afford the desired 2-(difluoromethoxy)-6-methyl-N-(2,2,2-trifluoroethyl)benzamide.
  • Step i 4-(7-bromoimidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide
  • the aqueous phase is extracted with a i-PrOH/DCM mixture. Organic layers are combined, dried over Na 2 SO 4 , filtered and concentrated. The crude material is purified by chromatography on silica gel (eluting with a gradient of 0 to 4% MeOH in DCM) to afford the desired product.
  • reaction mixture is cooled to 40° C. and concentrated (200 mL of toluene are used to wash the reactor). Toluene (1 V, 900 mL) is added to the residue and the solution is concentrated.
  • the liquid residue (940 g) is dissolved in DCM (5 V, 4.5 L) under N 2 and placed into the 15 L reactor.
  • the reaction mixture is cooled to 13° C. (jacket temperature: 5° C.) and a mixture of Et 3 N (582.22 mL, 4.18 mol, 1.1 eq.) and cyclopropylamine (CAS #765-30-0; 276.21 mL, 3.99 mol, 1.1 eq.) is added over 1.3 h keeping the temperature below 25° C. (jacket temperature set at 5° C. during the addition).
  • the reaction mixture is stirred under N 2 at 20° C. for 14 h.
  • a solvent exchange is performed in the 15 L reactor: to the DCM layer is added 1 L of heptane. The mixture is heated progressively with the jacket temperature set at 65° C. and DCM is removed between 43° C. and 50° C. After removing 2 L of DCM, 1 L of heptane is added. After removing a total of 4 L of solvent, 1 L of heptane is added and the mixture is cooled to 20° C. in 20 min. Finally 1 L of heptane (a total of 4 L of heptane is added) is added and the mixture is stirred at 20° C. for 45 min.
  • the suspension is filtered and the cake is washed with 1.5 L of heptane.
  • 6-methoxysalicyclic acid (CAS #3147-64-6; 10 g, 0.06 mmol, 1 eq.) is dissolved in DMF (50 mL), HATU (33.93 g, 0.09 mmol, 1.5 eq.) is added, followed 15 min later by cyclopropylamine (CAS #765-30-0; 10.18 g, 0.18 mmol, 3 eq.), and DIPEA (34.55 g, 0.26 mmol, 4.5 eq.). The reaction mixture is allowed to stir at RT for 18 h; then 1 eq. of HATU, 2 eq. of cyclopropylamine and 2 eq. of DIPEA are added.
  • the reaction mixture is stirred at RT for 68 h.
  • the reaction mixture is concentrated in vacuo.
  • Purification is performed by flash chromatography on silica gel (eluting with heptane/EtOAc 100/0 to 50/50).
  • the collected fractions are concentrated in vacuo and triturated twice with MeOH/Et 2 O.
  • the filtrate is concentrated in vacuo to afford the desired product.
  • N-cyclopropyl-2-hydroxy-6-methoxy-benzamide (2.80 g, 0.013 mmol, 1 eq.) is dissolved in ACN (20 mL) and cooled to ⁇ 20° C.
  • the reaction mixture is stirred at ⁇ 20° C. for 30 min then at RT for another 30 min.
  • Step iii Int 89: mixture of N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenylboronic acid
  • N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide (2.80 g, 10.89 mmol, 1 eq.)
  • B 2 pin 2 (8.30 g, 32.68 mmol, 3 eq.)
  • [Ir(OCH3)(COD)] (360 mg, 0.54 mmol, 0.05 eq.)
  • BBBPY 120 mg, 0.45 mmol, 0.04 eq.
  • the reaction mixture is stirred at 70° C. under N 2 for 3 h then at RT overnight. Purification by flash chromatography on silica gel (eluting with a gradient heptane/EtOAc 100/0 to 30/70) affords the expected product in mixture with the corresponding boronic acid.
  • the aqueous phase is then basified with a sat. aq. NaHCO 3 solution and extracted with AcOEt. The combined organic layers are dried over Na 2 SO 4 , filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluting with a gradient of 1 to 3% MeOH in DCM) to give the expected product Int 90.

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